Analyte Signal Processing Device and Methods

ABSTRACT

Methods and devices for determining a measurement time period, receiving a plurality of signals associated with a monitored analyte level during the determined measurement time period from an analyte sensor, modulating the received plurality of signals to generate a data stream over the measurement time period, and accumulating the generated data stream to determine an analyte signal corresponding to the monitored analyte level associated with the measurement time period are provided. Systems and kits are also described.

RELATED APPLICATION

The present application claims the benefit of U.S. ProvisionalApplication No. 61/238,658 filed Aug. 29, 2009, entitled “Analyte SignalProcessing Device and Methods”, the disclosure of which is incorporatedherein by reference for all purposes.

BACKGROUND

The monitoring of the level of glucose or other analytes, such aslactate or oxygen, in certain individuals is vitally important to theirhealth. High or low levels of glucose or other analytes may havedetrimental effects. The monitoring of glucose is particularly importantto individuals with diabetes, as they must determine when insulin isneeded to reduce glucose levels in their bodies or when additionalglucose is needed to raise the level of glucose in their bodies.

A conventional technique used by many diabetics for personallymonitoring their blood glucose level includes the periodic drawing ofblood, the application of that blood to a test strip, and thedetermination of the blood glucose level using calorimetric,electrochemical, or photometric detection. This technique does notpermit continuous or automatic monitoring of glucose levels in the body,but typically must be performed manually on a periodic basis.Unfortunately, the consistency with which the level of glucose ischecked varies widely among individuals. Many diabetics find theperiodic testing inconvenient and they sometimes forget to test theirglucose level or do not have time for a proper test. In addition, someindividuals wish to avoid the pain associated with the test. Thesesituations may result in hyperglycemic or hypoglycemic episodes. An invivo glucose sensor that continuously or automatically monitors theindividual's glucose level would enable individuals to more easilymonitor their glucose, or other analyte, levels.

A variety of devices have been developed for continuous or automaticmonitoring of analytes, such as glucose, in the blood stream orinterstitial fluid. A number of these devices use electrochemicalsensors which are directly implanted into a blood vessel or in thesubcutaneous tissue of a patient. However, these devices are oftendifficult to reproducibly and inexpensively manufacture in largenumbers. In addition, these devices are typically large, bulky, and/orinflexible, and many can not be used effectively outside of a controlledmedical facility, such as a hospital or a doctor's office, unless thepatient is restricted in his activities.

The patient's comfort and the range of activities that can be performedwhile the sensor is implanted are important considerations in designingextended-use sensors for continuous or automatic in vivo monitoring ofthe level of an analyte, such as glucose. There is a need for a small,comfortable device which can continuously monitor the level of ananalyte, such as glucose, while still permitting the patient to engagein normal activities. Continuous and/or automatic monitoring of theanalyte can provide a warning to the patient when the level of theanalyte is at or near a threshold level. For example, if glucose is theanalyte, then the monitoring device might be configured to warn thepatient of current or impending hyperglycemia or hypoglycemia. Thepatient can then take appropriate actions.

SUMMARY

An analyte signal processing method in one aspect of the presentdisclosure includes determining a measurement time period, receiving aplurality of signals associated with a monitored analyte level duringthe determined measurement time period from an analyte sensor,modulating the received plurality of signals to generate a data streamover the measurement time period, and accumulating the generated datastream to determine an analyte signal corresponding to the monitoredanalyte level associated with the measurement time period.

A signal processing device used for processing analyte related signalsin accordance with another aspect includes an analyte sensor interfaceelectronics for receiving a plurality of analyte related signals from ananalyte sensor over a measurement time period, a data processingcomponent operatively coupled to the analyte sensor interfaceelectronics for processing the received plurality of analyte relatedsignals, the data processing component including a signal filteringcomponent to filter the received plurality of analyte related signals, asignal conversion component operatively coupled to the signal filteringcomponent to convert the received filtered plurality of analyte relatedsignals to determine an analyte level associated with a monitoredanalyte level during the measurement time period.

An analyte monitoring system in still another aspect includes an analytesensor including a working electrode having a sensing layer at least aportion of which is configured for fluid contact with an with aninterstitial fluid under a skin layer, and a data processing unitcomprising an application specific integrated circuit (ASIC) in signalcommunication with the analyte sensor for receiving a plurality ofsignals related to a monitored analyte level from the sensor over amonitoring time period, the data processing unit including: a signalfiltering component to filter the received plurality of signals; and asignal conversion component to convert the received filtered pluralityof analyte related signals to determine a corresponding analyte levelassociated with a monitored analyte level during a measurement timeperiod, said monitoring time period including multiple measurement timeperiods.

These and other features, objects and advantages of the variousembodiments of the present disclosure will become apparent to thosepersons skilled in the art upon reading the details of the presentdisclosure as more fully described below.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows a block diagram of an embodiment of a data monitoring andmanagement system according to the present disclosure;

FIG. 2 shows a block diagram of an embodiment of the transmitter unit ofthe data monitoring and management system of FIG. 1;

FIGS. 3A and 3B illustrate the sensor/transmitter interface includingthe analog interface section of the data processing unit 102 of FIG. 2in one embodiment of the present disclosure;

FIG. 4 shows a block diagram of an embodiment of the receiver/monitorunit of the data monitoring and management system of FIG. 1;

FIG. 5 shows a schematic diagram of an embodiment of an analyte sensoraccording to the present disclosure; and

FIGS. 6A and 6B show a perspective view and a cross sectional view,respectively, of another embodiment an analyte sensor.

INCORPORATED BY REFERENCE

The following patents, applications and/or publications are incorporatedherein by reference for all purposes: U.S. Pat. Nos. 5,262,035;5,262,305; 5,264,104; 5,320,715; 5,543,326; 5,593,852; 6,103,033;6,120,676; 6,134,461; 6,175,752; 6,284,478; 6,560,471; 6,579,690;6,591,125; 6,605,200; 6,605,201; 6,650,471; 6,654,625; 6,676,819;6,746,582; 6,881,551; 6,932,892; 6,932,894; 7,299,082; U.S. PublishedPatent Application Nos. 2004/0186365; 2005/0182306; 2007/0056858;2007/0068807; 2007/0227911; 2007/0233013; 2008/0081977; 2008/0161666;and 2009/0054748; U.S. patent application Ser. Nos. 12/131,012;12/242,823; and 12/363,712; and U.S. Provisional Application Ser. Nos.61/149,639; 61/155,889; 61/155,891; 61/155,893; 61/165,499; 61/230,686;61/227,967 and 61/238,461.

DETAILED DESCRIPTION

Before the present disclosure is described, it is to be understood thatthis disclosure is not limited to particular embodiments described, assuch may, of course, vary. It is also to be understood that theterminology used herein is for the purpose of describing particularembodiments only, and is not intended to be limiting, since the scope ofthe present disclosure will be limited only by the appended claims.

Where a range of values is provided, it is understood that eachintervening value, to the tenth of the unit of the lower limit unlessthe context clearly dictates otherwise, between the upper and lowerlimit of that range and any other stated or intervening value in thatstated range, is encompassed within the disclosure. The upper and lowerlimits of these smaller ranges may independently be included in thesmaller ranges is also encompassed within the disclosure, subject to anyspecifically excluded limit in the stated range. Where the stated rangeincludes one or both of the limits, ranges excluding either or both ofthose included limits are also included in the disclosure.

It must be noted that as used herein and in the appended claims, thesingular forms “a”, “an”, and “the” include plural referents unless thecontext clearly dictates otherwise.

As will be apparent to those of skill in the art upon reading thisdisclosure, each of the individual embodiments described and illustratedherein has discrete components and features which may be readilyseparated from or combined with the features of any of the other severalembodiments without departing from the scope or spirit of the presentdisclosure.

The figures shown herein are not necessarily drawn to scale, with somecomponents and features being exaggerated for clarity.

Generally, embodiments of the present disclosure relate to methods anddevices for detecting at least one analyte such as glucose in bodyfluid. Embodiments relate to the continuous and/or automatic in vivomonitoring of the level of one or more analytes using a continuousanalyte monitoring system that includes an analyte sensor at least aportion of which is to be positioned beneath a skin surface of a userfor a period of time and/or the discrete monitoring of one or moreanalytes using an in vitro blood glucose (“BG”) meter and an analytetest strip. Embodiments include combined or combinable devices, systemsand methods and/or transferring data between an in vivo continuoussystem and a BG meter system.

Accordingly, embodiments include analyte monitoring devices and systemsthat include an analyte sensor—at least a portion of which ispositionable beneath the skin of the user—for the in vivo detection, ofan analyte, such as glucose, lactate, and the like, in a body fluid.Embodiments include wholly implantable analyte sensors and analytesensors in which only a portion of the sensor is positioned under theskin and a portion of the sensor resides above the skin, e.g., forcontact to a transmitter, receiver, transceiver, processor, etc. Thesensor may be, for example, subcutaneously positionable in a patient forthe continuous or periodic monitoring of a level of an analyte in apatient's interstitial fluid. For the purposes of this description,continuous monitoring and periodic monitoring will be usedinterchangeably, unless noted otherwise. The sensor response may becorrelated and/or converted to analyte levels in blood or other fluids.In certain embodiments, an analyte sensor may be positioned in contactwith interstitial fluid to detect the level of glucose, which detectedglucose may be used to infer the glucose level in the patient'sbloodstream. Analyte sensors may be insertable into a vein, artery, orother portion of the body containing fluid. Embodiments of the analytesensors of the subject disclosure may be configured for monitoring thelevel of the analyte over a time period which may range from minutes,hours, days, weeks, or longer.

Of interest are analyte sensors, such as glucose sensors, that arecapable of in vivo detection of an analyte for about one hour or more,e.g., about a few hours or more, e.g., about a few days of more, e.g.,about three or more days, e.g., about five days or more, e.g., aboutseven days or more, e.g., about several weeks or at least one month.Future analyte levels may be predicted based on information obtained,e.g., the current analyte level at time t₀, the rate of change of theanalyte, etc. Predictive alarms may notify the user of a predictedanalyte levels that may be of concern in advance of the user's analytelevel reaching the future level. This provides the user an opportunityto take corrective action.

FIG. 1 shows a data monitoring and management system such as, forexample, an analyte (e.g., glucose) monitoring system 100 in accordancewith certain embodiments. Embodiments of the subject disclosure arefurther described primarily with respect to glucose monitoring devicesand systems, and methods of glucose detection, for convenience only andsuch description is in no way intended to limit the scope of thedisclosure. It is to be understood that the analyte monitoring systemmay be configured to monitor a variety of analytes at the same time orat different times.

Analytes that may be monitored include, but are not limited to, acetylcholine, amylase, bilirubin, cholesterol, chorionic gonadotropin,creatine kinase (e.g., CK-MB), creatine, creatinine, DNA, fructosamine,glucose, glutamine, growth hormones, hormones, ketone bodies, lactate,peroxide, prostate-specific antigen, prothrombin, RNA, thyroidstimulating hormone, and troponin. The concentration of drugs, such as,for example, antibiotics (e.g., gentamicin, vancomycin, and the like),digitoxin, digoxin, drugs of abuse, theophylline, and warfarin, may alsobe monitored. In those embodiments that monitor more than one analyte,the analytes may be monitored at the same or different times.

The analyte monitoring system 100 includes a sensor 101, a dataprocessing unit 102 connectable to sensor 101, and a primary receiverunit 104 which is configured to communicate with data processing unit102 via a communication link 103. In certain embodiments, primaryreceiver unit 104 may be further configured to transmit data to a dataprocessing terminal 105 to evaluate or otherwise process or format datareceived by primary receiver unit 104. Data processing terminal 105 maybe configured to receive data directly from data processing unit 102 viaa communication link which may optionally be configured forbi-directional communication. Further, data processing unit 102 mayinclude a transmitter or a transceiver to transmit and/or receive datato and/or from primary receiver unit 104 and/or data processing terminal105 and/or optionally the secondary receiver unit 106.

Also shown in FIG. 1 is an optional secondary receiver unit 106 which isoperatively coupled to the communication link and configured to receivedata transmitted from data processing unit 102. The secondary receiverunit 106 may be configured to communicate with primary receiver unit104, as well as data processing terminal 105. The secondary receiverunit 106 may be configured for bi-directional wireless communicationwith each of primary receiver unit 104 and data processing terminal 105.As discussed in further detail below, in certain embodiments thesecondary receiver unit 106 may be a de-featured receiver as compared tothe primary receiver, i.e., the secondary receiver may include a limitedor minimal number of functions and features as compared with primaryreceiver unit 104. As such, the secondary receiver unit 106 may includea smaller (in one or more, including all, dimensions), compact housingor embodied in a device such as a wrist watch, arm band, etc., forexample. Alternatively, the secondary receiver unit 106 may beconfigured with the same or substantially similar functions and featuresas primary receiver unit 104. The secondary receiver unit 106 mayinclude a docking portion to be mated with a docking cradle unit forplacement by, e.g., the bedside for night time monitoring, and/or abi-directional communication device. A docking cradle may recharge apowers supply.

Only one sensor 101, data processing unit 102 and data processingterminal 105 are shown in the embodiment of the analyte monitoringsystem 100 illustrated in FIG. 1. However, it will be appreciated by oneof ordinary skill in the art that the analyte monitoring system 100 mayinclude more than one sensor 101 and/or more than one data processingunit 102, and/or more than one data processing terminal 105. Multiplesensors may be positioned in a patient for analyte monitoring at thesame or different times. In certain embodiments, analyte informationobtained by a first positioned sensor may be employed as a comparison toanalyte information obtained by a second sensor. This may be useful toconfirm or validate analyte information obtained from one or both of thesensors. Such redundancy may be useful if analyte information iscontemplated in critical therapy-related decisions. In certainembodiments, a first sensor may be used to calibrate a second sensor.

The analyte monitoring system 100 may be a continuous monitoring system,or semi-continuous, or a discrete monitoring system. In amulti-component environment, each component may be configured to beuniquely identified by one or more of the other components in the systemso that communication conflict may be readily resolved between thevarious components within the analyte monitoring system 100. Forexample, unique IDs, communication channels, and the like, may be used.

In certain embodiments, sensor 101 is physically positioned in or on thebody of a user whose analyte level is being monitored. Sensor 101 may beconfigured to at least periodically sample the analyte level of the userand convert the sampled analyte level into a corresponding signal fortransmission by data processing unit 102. Data processing unit 102 iscoupleable to sensor 101 so that both devices are positioned in or onthe user's body, with at least a portion of the analyte sensor 101positioned transcutaneously. The data processing unit may include afixation element such as adhesive or the like to secure it to the user'sbody. A mount (not shown) attachable to the user and mateable with dataprocessing unit 102 may be used. For example, a mount may include anadhesive surface. Data processing unit 102 performs data processingfunctions, where such functions may include but are not limited to,filtering and encoding of data signals, each of which corresponds to asampled analyte level of the user, for transmission to primary receiverunit 104 via the communication link 103. In one embodiment, sensor 101or data processing unit 102 or a combined sensor/data processing unitmay be wholly implantable under the skin layer of the user.

In certain embodiments, primary receiver unit 104 may include an analoginterface section including and RF receiver and an antenna that isconfigured to communicate with data processing unit 102 via thecommunication link 103, and a data processing section for processing thereceived data from data processing unit 102 such as data decoding, errordetection and correction, data clock generation, data bit recovery,etc., or any combination thereof.

In operation, primary receiver unit 104 in certain embodiments isconfigured to synchronize with data processing unit 102 to uniquelyidentify data processing unit 102, based on, for example, anidentification information of data processing unit 102, and thereafter,to periodically receive signals transmitted from data processing unit102 associated with the monitored analyte levels detected by sensor 101.

Referring again to FIG. 1, data processing terminal 105 may include apersonal computer, a portable computer such as a laptop or a handhelddevice (e.g., personal digital assistants (PDAs), telephone such as acellular phone (e.g., a multimedia and Internet-enabled mobile phonesuch as an iPhone or similar phone), mp3 player, pager, and the like),drug delivery device, each of which may be configured for datacommunication with the receiver via a wired or a wireless connection.Additionally, data processing terminal 105 may further be connected to adata network (not shown) for storing, retrieving, updating, and/oranalyzing data corresponding to the detected analyte level of the user.

In certain embodiments, data processing terminal 105 may include aninfusion device such as an insulin infusion pump or the like, which maybe configured to administer insulin to patients, and which may beconfigured to communicate with primary receiver unit 104 for receiving,among others, the measured analyte level. Alternatively, primaryreceiver unit 104 may be configured to integrate an infusion devicetherein so that primary receiver unit 104 is configured to administerinsulin (or other appropriate drug) therapy to patients, for example,for administering and modifying basal profiles, as well as fordetermining appropriate boluses for administration based on, amongothers, the detected analyte levels received from data processing unit102. An infusion device may be an external device or an internal device(wholly implantable in a user).

In certain embodiments, data processing terminal 105, which may includean insulin pump, may be configured to receive the analyte signals fromdata processing unit 102, and thus, incorporate the functions of primaryreceiver unit 104 including data processing for managing the patient'sinsulin therapy and analyte monitoring. In certain embodiments, thecommunication link 103 as well as one or more of the other communicationinterfaces shown in FIG. 1, may use one or more of: an RF communicationprotocol, an infrared communication protocol, a Bluetooth enabledcommunication protocol, an 802.11x wireless communication protocol, oran equivalent wireless communication protocol which would allow secure,wireless communication of several units (for example, per HIPPArequirements), while avoiding potential data collision and interference.

FIG. 2 shows a block diagram of an embodiment of a data processing unitof the data monitoring and detection system shown in FIG. 1. User inputand/or interface components may be included or a data processing unitmay be free of user input and/or interface components. In certainembodiments, one or more ASICs may be used to implement one or morefunctions or routines associated with the operations of the dataprocessing unit (and/or receiver unit) using for example one or morestate machines and buffers.

As can be seen in the embodiment of FIG. 2, the sensor 101 (FIG. 1)includes four contacts, three of which are electrodes—work electrode (W)210, reference electrode (R) 212, and counter electrode (C) 213, eachoperatively coupled to the analog interface 201 of data processing unit102. This embodiment also shows optional guard contact (G) 211. Fewer orgreater electrodes may be employed. For example, the counter andreference electrode functions may be served by a singlecounter/reference electrode, there may be more than one workingelectrode and/or reference electrode and/or counter electrode, etc.

The electronics of the on-skin sensor control unit and the sensor areoperated using a power supply 207, e.g., a battery.

In one aspect, the analog interface 201 is coupled via the conductivecontacts of data processing unit 102 to one or more sensors 101. Theanalog interface 201 in one embodiment is configured to receive signalsfrom and to operate the sensor(s). For example, in one embodiment, theanalyte interface 201 may obtain signals from sensor 101 (FIG. 1) usingamperometric, coulometric, potentiometric, voltammetric, and/or otherelectrochemical techniques. For example, to obtain amperometricmeasurements, the analog interface 201 includes a potentiostat thatprovides a constant potential to sensor 101. In other embodiments, theanalog interface 201 includes an amperostat that supplies a constantcurrent to a sensor and can be used to obtain coulometric orpotentiometric measurements.

The signal from the sensor 101 (FIG. 1) generally has at least onecharacteristic, such as, for example, current, voltage, or frequency, orthe like, which varies with the concentration of the analyte that thesensor 101 is monitoring. For example, if the analog interface 201operates using amperometry, then the current signal from the sensorvaries with variation in the monitored analyte concentration. Referringback to FIG. 2, one or more of the components of data processing unit102, including, for example, the processor 204, the analog interface201, and/or the RF transmitter/receiver 206 may include circuitry whichconverts the information-carrying portion of the signal from onecharacteristic to another. For example, the one or more components ofdata processing unit 102 such as the processor 204, the analyteinterface 201, and/or the RF transmitter/receiver 206 may include acurrent-to-voltage or current-to-frequency converter. In one aspect, theconverter may be configured to provide a signal that is, for example,more easily transmitted, readable by digital circuits, and/or lesssusceptible to noise contributions.

Referring now to FIGS. 3A and 3B, the sensor interface electronicsincluding the analog interface section of the data processing unit 102(FIG. 1). More specifically, referring to FIG. 3A, there is provided ananalog to digital converter (ADC) 310 which is configured to receive thefiltered output analog signal of the operational amplifier 320 which hasone of its input terminals (negative input terminal as shown, forexample) operatively coupled to the working electrode W 210 of sensor101 (FIG. 1). As described, in one aspect, the operational amplifier 320is configured to maintain the voltage level at the working electrode W210 at approximately two volts while the reference electrode R 212 (FIG.2) of the sensor (FIG. 1) is operatively coupled to the positive inputterminal of the operational amplifier 320 and maintained atapproximately 1.96 Volts, so that a difference of approximately 40mVolts is maintained as the poise voltage to power the sensorelectrodes.

Referring back to FIG. 3A, the filter 330 operatively coupled betweenthe negative input terminal and the output terminal of the operationalamplifier 320, is configured to filter the received signal from thesensor electrodes to remove or filter out the signal transients. Signalartifacts may be limited to a predetermined signal bandwidth (forexample, to approximately 0.1 Hz) effectively operating as a bandpassfilter prior to providing the signal to the analog to digital converterADC 310 for further processing.

In one embodiment, the resistor R of the filter 330 has a resistancevalue of approximately 1.58 MOhms, while the capacitor C has acapacitance of approximately one microFarad. While specific values areprovided herein, it is to be noted that these values for the variouscomponents of the filter as well as the operational amplifier are forexemplary purposes only, and are not intended to limit the scope of theembodiments of the present disclosure to such particular values orparameters. Within the scope of the present disclosure, other values orparameters are contemplated for example, for the resistor R and thecapacitor C of the filter 330, as well as the operational amplifier 320.

Referring still to FIG. 3A, the filtered output signal from theoperational amplifier 320 in the form of an analog voltage signal isprovided to the analog to digital converter 310 for further processingas described herein. That is, referring now to FIG. 3B, a detaileddescription of a portion of the ADC 310 is shown. More specifically, asshown in FIG. 3B, the ADC 310 includes, among others, a signal modulator311 operatively coupled to the input of the ADC 310 to receive thevoltage signal from the output of the operational amplifier 320 (FIG.3A). The signal modulator in one embodiment may include a Sigma-Deltamodulator. A Sigma-Delta modulator, in certain embodiments, allows forhigh resolution analog-to-digital conversion achievable utilizing lowcost circuits. In other embodiments, different or modified modulatorswith similar or equivalent functionality may be provided including, forexample, converters, filters, and/or signal processing devices andcomponents.

In one aspect, the modulator 311 is configured to modulate the receivedanalog voltage signal from the output of the operational amplifier 320to generate a corresponding frequency data stream which is synchronizedwith one or more clock signals. That is, referring to FIG. 3B, in oneaspect, the modulator 311 is configured to convert the received voltagesignal which may vary between, for example, 1.5 Volts to 2.0 Volts, intoa corresponding frequency data stream. In one aspect, the modulator 311includes a servo loop and the output of the modulator 311 includes theconverted or modulated frequency data stream and the corresponding clocksignal.

Referring again to FIG. 3B, AND gate 312 is shown and provided to theADC 310, and is configured to receive the frequency data stream (shownas “data” in FIG. 3B) and the clock signal (shown as “clk” in FIG. 3B)and perform an AND function to synchronize the received frequency datawith the clock signal to generate a corresponding frequency pulse toprovide to a counter 313. That is, as shown in FIG. 3B, the outputterminal of the AND gate 312 is operatively coupled to the counter 313,and the counter 313, in one embodiment is configured to count the pulsesreceived from the AND gate 312. In some embodiments, the analog todigital conversion is conducted quickly, in order to obtain a convertedsignal for a specific point in time. In order for the analog to digitalconversion to be achieved substantially immediately, a high frequencyclock signal is used, such that the counted pulses of the conversionoccur in rapid succession.

In other embodiments, a lower frequency clock, for example a 1024 Hzclock signal, may be implemented and the analog to digital conversion isspread out over a predetermined or programmed time period, such as, forexample, a 30 second (or other suitable or appropriate) time period orother suitable measurement time period. In one aspect, the counter 313is configured to receive the synchronized frequency data stream orpulses from the AND gate 312 and counts the received pulses over thepredetermined time period to generate an average accumulated count, thatis representative of the average data associated with the signal fromsensor 101 (FIG. 1) over the time period.

In one aspect, the clock signal used to synchronize the data stream fromthe modulator 311 is a 1024 Hz signal. Furthermore, in one embodiment,the AND gate 312 operates such that the pulse from the modulator 311 isreceived by the counter 313 when the clock signal is a “1” (as opposedto a “0”). In this manner, in one aspect, the counter 313 is initiallyset to a zero count, and thereafter, when the predetermined measurementtime period has elapsed (for example, the 30 second time period), thecounter 313 has accumulated pulses during this time duration to outputan average value of the accumulated pulses received from the timeduration as the corresponding sensor data processed from the voltagesignal received from the working electrode 210 (FIG. 2) of sensor 101(FIG. 1).

In this manner, in one aspect, lower power consumption of the dataprocessing unit 102 (FIG. 1) may be achieved, in addition to improvingprocessed analyte signal resolution as well as providing a built-infiltering function to filter out signal transients and/or noiseassociated with the received signals. That is, given that the counter isconfigured to accumulate the pulses over an extended measurement timeperiod such as 30 seconds or other suitable time period, and given thatthe determined or programmed time period defines the filter frequencyresponse, by customizing or tailoring the time period to a particularsensor or sensors, the frequency response associated with the sensor maybe improved. Moreover, the predetermined or programmed time periodprovides a time duration which allows the use of low frequency modulatorclock (e.g., 1024 Hz) which consumes less power, and thus, extends thepower supply life of the data processing unit 102 (FIG. 1).

Referring still again to FIGS. 3A and 3B, in the manner described above,in aspects of the present disclosure, an extended measurement timeperiod is provided based on, for example, the predetermined orprogrammed time period to sample or accumulate the pulses or data streamreceived from analyte sensor 101, and that is determined by or is afunction of the clock discussed above in conjunction with the modulatorand configured to establish the maximum resolution as a function of theconversion (analog to digital) time. In this manner, in one aspect, anextended sampling time period (as compared to a discrete signalsampling) is provided to extend the signal conversion process over alonger measurement time period resulting in improved power consumptionmanagement, higher signal resolution and noise or artifact filteredanalyte signals for further processing, including transmission to aremote device or location for presentation or output to the user orpatient.

Accumulating or averaging the received frequency data stream or pulsesfrom analyte sensor 101 results in a frequency domain filter functionthat rolls off at a frequency equal to the reciprocal of the signalconversion time. Thus, any frequency or components of the data streamthat is a multiple of the signal conversion time is rejected, filteringout undesirable signal artifacts, among others. Additionally, given thatcommon signal frequency interference occurs at the power linefrequencies of 50 and 60 Hz, and multiples thereof, by modifying oradjusting the conversion time duration to be a division of the commoninterference frequencies, the filter function is configured to removethese frequency signals.

Additionally, as discussed above, the embodiments described aboveprovides low power consumption by providing a slow modulator clock whileretaining the desired high signal resolution, as the slow clock consumesa low amount of power such that, using 1024 Hz clock with a 30 secondconversion time period, a 15 bit signal resolution may be attained. Inaspects of the present disclosure, the clock function of the modulator311 may be a divided down clock as described above, divided down from a32.768 KHz crystal to the 1024 Hz clock.

Referring back to FIGS. 3A and 3B, the converted analyte related signalfrom the output of the ADC 310 is further processed for storage,additional filtering, and data packing, encoding and the like forwireless transmission, for example to the receiver/monitor unit 104, aswell as other data processing routines described herein.

FIG. 4 is a block diagram of an embodiment of a receiver/monitor unitsuch as primary receiver unit 104 of the data monitoring and managementsystem shown in FIG. 1. In certain embodiments, primary receiver unit104 includes one or more of: a blood glucose test strip interface 401,an RF receiver 402, an input 403, a temperature detection section 404,and a clock 405, each of which is operatively coupled to a processingand storage section 407. Primary receiver unit 104 also includes a powersupply 406 operatively coupled to a power conversion and monitoringsection 408. Further, the power conversion and monitoring section 408 isalso coupled to the receiver processor 407. Moreover, also shown are areceiver serial communication section 409, and an output 410, eachoperatively coupled to the processing and storage unit 407. The receivermay include user input and/or interface components or may be free ofuser input and/or interface components.

In certain embodiments, the test strip interface 401 includes a glucoselevel testing portion to receive a blood (or other body fluid sample)glucose test or information related thereto. For example, the interfacemay include a test strip port to receive a glucose test strip. Thedevice may determine the glucose level of the test strip, and optionallydisplay (or otherwise notice) the glucose level on the output 410 ofprimary receiver unit 104. Any suitable test strip may be employed,e.g., test strips that only require a very small amount (e.g., onemicroliter or less, e.g., 0.5 microliter or less, e.g., 0.1 microliteror less), of applied sample to the strip in order to obtain accurateglucose information, e.g. FreeStyle® blood glucose test strips fromAbbott Diabetes Care Inc. Glucose information obtained by the in vitroglucose testing device may be used for a variety of purposes,computations, etc. For example, the information may be used to calibratesensor 101, confirm results of sensor 101 to increase the confidencethereof (e.g., in instances in which information obtained by sensor 101is employed in therapy related decisions), etc.

In further embodiments, data processing unit 102 and/or primary receiverunit 104 and/or the secondary receiver unit 105, and/or the dataprocessing terminal/infusion section 105 may be configured to receivethe blood glucose value wirelessly over a communication link from, forexample, a blood glucose meter. In further embodiments, a usermanipulating or using the analyte monitoring system 100 (FIG. 1) maymanually input the blood glucose value using, for example, a userinterface (for example, a keyboard, keypad, voice commands, and thelike) incorporated in the one or more of data processing unit 102,primary receiver unit 104, secondary receiver unit 105, or the dataprocessing terminal/infusion section 105.

FIG. 5 schematically shows an embodiment of an analyte sensor inaccordance with the present disclosure. This sensor embodiment includeselectrodes 501, 502 and 503 on a base 504. Electrodes (and/or otherfeatures) may be applied or otherwise processed using any suitabletechnology, e.g., chemical vapor deposition (CVD), physical vapordeposition, sputtering, reactive sputtering, photolithography, printing,coating, ablating (e.g., laser ablation), painting, dip coating,etching, and the like. Materials include but are not limited toaluminum, carbon (such as graphite), cobalt, copper, gallium, gold,indium, iridium, iron, lead, magnesium, mercury (as an amalgam), nickel,niobium, osmium, palladium, platinum, rhenium, rhodium, selenium,silicon (e.g., doped polycrystalline silicon), silver, tantalum, tin,titanium, tungsten, uranium, vanadium, zinc, zirconium, mixturesthereof, and alloys, oxides, or metallic compounds of these elements.

The sensor may be wholly implantable in a user or may be configured sothat only a portion is positioned within (internal) a user and anotherportion outside (external) a user. For example, the sensor 500 mayinclude a portion positionable above a surface of the skin 510, and aportion positioned below the skin. In such embodiments, the externalportion may include contacts (connected to respective electrodes of thesecond portion by traces) to connect to another device also external tothe user such as a transmitter unit. While the embodiment of FIG. 5shows three electrodes side-by-side on the same surface of base 504,other configurations are contemplated, e.g., fewer or greaterelectrodes, some or all electrodes on different surfaces of the base orpresent on another base, some or all electrodes stacked together,electrodes of differing materials and dimensions, etc.

FIG. 6A shows a perspective view of an embodiment of an electrochemicalanalyte sensor 600 having a first portion (which in this embodiment maybe characterized as a major portion) positionable above a surface of theskin 610, and a second portion (which in this embodiment may becharacterized as a minor portion) that includes an insertion tip 630positionable below the skin, e.g., penetrating through the skin andinto, e.g., the subcutaneous space 620, in contact with the user'sbiofluid such as interstitial fluid. Contact portions of a workingelectrode 601, a reference electrode 602, and a counter electrode 603are positioned on the portion of the sensor 600 situated above the skinsurface 610. Working electrode 601, a reference electrode 602, and acounter electrode 603 are shown at the second section and particularlyat the insertion tip 630. Traces may be provided from the electrode atthe tip to the contact, as shown in FIG. 6A. It is to be understood thatgreater or fewer electrodes may be provided on a sensor. For example, asensor may include more than one working electrode and/or the counterand reference electrodes may be a single counter/reference electrode,etc.

FIG. 6B shows a cross sectional view of a portion of the sensor 600 ofFIG. 6A. The electrodes 610, 602 and 603, of the sensor 600 as well asthe substrate and the dielectric layers are provided in a layeredconfiguration or construction. For example, as shown in FIG. 6B, in oneaspect, the sensor 600 (such as the sensor 101 FIG. 1), includes asubstrate layer 604, and a first conducting layer 601 such as carbon,gold, etc., disposed on at least a portion of the substrate layer 604,and which may provide the working electrode. Also shown disposed on atleast a portion of the first conducting layer 601 is a sensing layer608.

A first insulation layer such as a first dielectric layer 605 isdisposed or layered on at least a portion of the first conducting layer601, and further, a second conducting layer 609 may be disposed orstacked on top of at least a portion of the first insulation layer (ordielectric layer) 605. As shown in FIG. 6B, the second conducting layer609 may provide the reference electrode 602, and in one aspect, mayinclude a layer of silver/silver chloride (Ag/AgCl), gold, etc.

A second insulation layer 606 such as a dielectric layer in oneembodiment may be disposed or layered on at least a portion of thesecond conducting layer 609. Further, a third conducting layer 603 mayprovide the counter electrode 603. It may be disposed on at least aportion of the second insulation layer 606. Finally, a third insulationlayer may be disposed or layered on at least a portion of the thirdconducting layer 603. In this manner, the sensor 600 may be layered suchthat at least a portion of each of the conducting layers is separated bya respective insulation layer (for example, a dielectric layer). Theembodiment of FIGS. 5A and 5B show the layers having different lengths.Some or all of the layers may have the same or different lengths and/orwidths.

In certain embodiments, some or all of the electrodes 601, 602, 603 maybe provided on the same side of the substrate 604 in the layeredconstruction as described above, or alternatively, may be provided in aco-planar manner such that two or more electrodes may be positioned onthe same plane (e.g., side-by side (e.g., parallel) or angled relativeto each other) on the substrate 604. For example, co-planar electrodesmay include a suitable spacing there between and/or include dielectricmaterial or insulation material disposed between the conductinglayers/electrodes. Furthermore, in certain embodiments one or more ofthe electrodes 601, 602, 603 may be disposed on opposing sides of thesubstrate 604. In such embodiments, contact pads may be one the same ordifferent sides of the substrate. For example, an electrode may be on afirst side and its respective contact may be on a second side, e.g., atrace connecting the electrode and the contact may traverse through thesubstrate.

As noted above, analyte sensors may include an analyte-responsive enzymeto provide a sensing component or sensing layer. Some analytes, such asoxygen, can be directly electrooxidized or electroreduced on a sensor,and more specifically at least on a working electrode of a sensor. Otheranalytes, such as glucose and lactate, require the presence of at leastone electron transfer agent and/or at least one catalyst to facilitatethe electrooxidation or electroreduction of the analyte. Catalysts mayalso be used for those analyte, such as oxygen, that can be directlyelectrooxidized or electroreduced on the working electrode. For theseanalytes, each working electrode includes a sensing layer (see forexample sensing layer 408 of FIG. 6B) proximate to or on a surface of aworking electrode. In many embodiments, a sensing layer is formed nearor on only a small portion of at least a working electrode.

The sensing layer includes one or more components designed to facilitatethe electrochemical oxidation or reduction of the analyte. The sensinglayer may include, for example, a catalyst to catalyze a reaction of theanalyte and produce a response at the working electrode, an electrontransfer agent to transfer electrons between the analyte and the workingelectrode (or other component), or both.

A variety of different sensing layer configurations may be used. Incertain embodiments, the sensing layer is deposited on the conductivematerial of a working electrode. The sensing layer may extend beyond theconductive material of the working electrode. In some cases, the sensinglayer may also extend over other electrodes, e.g., over the counterelectrode and/or reference electrode (or counter/reference is provided).

A sensing layer that is not in direct contact with the working electrodemay include a catalyst that facilitates a reaction of the analyte.However, such sensing layers may include an electron transfer agent thattransfers electrons directly from the analyte to the working electrode,as the sensing layer is spaced apart from the working electrode. Oneexample of this type of sensor is a glucose or lactate sensor whichincludes an enzyme (e.g., glucose oxidase, glucose dehydrogenase,lactate oxidase, and the like) in the sensing layer. The glucose orlactate may react with a second compound in the presence of the enzyme.The second compound may then be electrooxidized or electroreduced at theelectrode. Changes in the signal at the electrode indicate changes inthe level of the second compound in the fluid and are proportional tochanges in glucose or lactate level and, thus, correlate to the analytelevel.

In certain embodiments which include more than one working electrode,one or more of the working electrodes may not have a correspondingsensing layer, or may have a sensing layer which does not contain one ormore components (e.g., an electron transfer agent and/or catalyst)needed to electrolyze the analyte. Thus, the signal at this workingelectrode may correspond to background signal which may be removed fromthe analyte signal obtained from one or more other working electrodesthat are associated with fully-functional sensing layers by, forexample, subtracting the signal.

In certain embodiments, the sensing layer includes one or more electrontransfer agents. Electron transfer agents that may be employed areelectroreducible and electrooxidizable ions or molecules having redoxpotentials that are a few hundred millivolts above or below the redoxpotential of the standard calomel electrode (SCE). The electron transferagent may be organic, organometallic, or inorganic. Examples of organicredox species are quinones and species that in their oxidized state havequinoid structures, such as Nile blue and indophenol. Examples oforganometallic redox species are metallocenes such as ferrocene.Examples of inorganic redox species are hexacyanoferrate (III),ruthenium hexamine etc.

In certain embodiments, electron transfer agents have structures orcharges which prevent or substantially reduce the diffusional loss ofthe electron transfer agent during the period of time that the sample isbeing analyzed. For example, electron transfer agents include but arenot limited to a redox species, e.g., bound to a polymer which can inturn be disposed on or near the working electrode. The bond between theredox species and the polymer may be covalent, coordinative, or ionic.Although any organic, organometallic or inorganic redox species may bebound to a polymer and used as an electron transfer agent, in certainembodiments the redox species is a transition metal compound or complex,e.g., osmium, ruthenium, iron, and cobalt compounds or complexes. Itwill be recognized that many redox species described for use with apolymeric component may also be used, without a polymeric component.

One type of polymeric electron transfer agent contains a redox speciescovalently bound in a polymeric composition. An example of this type ofmediator is poly(vinylferrocene). Another type of electron transferagent contains an ionically-bound redox species. This type of mediatormay include a charged polymer coupled to an oppositely charged redoxspecies. Examples of this type of mediator include a negatively chargedpolymer coupled to a positively charged redox species such as an osmiumor ruthenium polypyridyl cation. Another example of an ionically-boundmediator is a positively charged polymer such as quaternizedpoly(4-vinyl pyridine) or poly(1-vinyl imidazole) coupled to anegatively charged redox species such as ferricyanide or ferrocyanide.In other embodiments, electron transfer agents include a redox speciescoordinatively bound to a polymer. For example, the mediator may beformed by coordination of an osmium or cobalt 2,2′-bipyridyl complex topoly(1-vinyl imidazole) or poly(4-vinyl pyridine).

Suitable electron transfer agents are osmium transition metal complexeswith one or more ligands, each ligand having a nitrogen-containingheterocycle such as 2,2′-bipyridine, 1,10-phenanthroline, 1-methyl,2-pyridyl biimidazole, or derivatives thereof. The electron transferagents may also have one or more ligands covalently bound in a polymer,each ligand having at least one nitrogen-containing heterocycle, such aspyridine, imidazole, or derivatives thereof. One example of an electrontransfer agent includes (a) a polymer or copolymer having pyridine orimidazole functional groups and (b) osmium cations complexed with twoligands, each ligand containing 2,2′-bipyridine, 1,10-phenanthroline, orderivatives thereof, the two ligands not necessarily being the same.Some derivatives of 2,2′-bipyridine for complexation with the osmiumcation include but are not limited to 4,4′-dimethyl-2,2′-bipyridine andmono-, di-, and polyalkoxy-2,2′-bipyridines, such as4,4′-dimethoxy-2,2′-bipyridine. Derivatives of 1,10-phenanthroline forcomplexation with the osmium cation include but are not limited to4,7-dimethyl-1,10-phenanthroline and mono, di-, andpolyalkoxy-1,10-phenanthrolines, such as4,7-dimethoxy-1,10-phenanthroline. Polymers for complexation with theosmium cation include but are not limited to polymers and copolymers ofpoly(1-vinyl imidazole) (referred to as “PVI”) and poly(4-vinylpyridine) (referred to as “PVP”). Suitable copolymer substituents ofpoly(1-vinyl imidazole) include acrylonitrile, acrylamide, andsubstituted or quaternized N-vinyl imidazole, e.g., electron transferagents with osmium complexed to a polymer or copolymer of poly(1-vinylimidazole).

Embodiments may employ electron transfer agents having a redox potentialranging from about −200 mV to about +200 mV versus the standard calomelelectrode (SCE). The sensing layer may also include a catalyst which iscapable of catalyzing a reaction of the analyte. The catalyst may also,in some embodiments, act as an electron transfer agent. One example of asuitable catalyst is an enzyme which catalyzes a reaction of theanalyte. For example, a catalyst, such as a glucose oxidase, glucosedehydrogenase (e.g., pyrroloquinoline quinone (PQQ), dependent glucosedehydrogenase, flavine adenine dinucleotide (FAD), or nicotinamideadenine dinucleotide (NAD) dependent glucose dehydrogenase), may be usedwhen the analyte of interest is glucose. A lactate oxidase or lactatedehydrogenase may be used when the analyte of interest is lactate.Laccase may be used when the analyte of interest is oxygen or whenoxygen is generated or consumed in response to a reaction of theanalyte.

The sensing layer may also include a catalyst which is capable ofcatalyzing a reaction of the analyte. The catalyst may also, in someembodiments, act as an electron transfer agent. One example of asuitable catalyst is an enzyme which catalyzes a reaction of theanalyte. For example, a catalyst, such as a glucose oxidase, glucosedehydrogenase (e.g., pyrroloquinoline quinone (PQQ), dependent glucosedehydrogenase or oligosaccharide dehydrogenase, flavine adeninedinucleotide (FAD) dependent glucose dehydrogenase, nicotinamide adeninedinucleotide (NAD) dependent glucose dehydrogenase), may be used whenthe analyte of interest is glucose. A lactate oxidase or lactatedehydrogenase may be used when the analyte of interest is lactate.Laccase may be used when the analyte of interest is oxygen or whenoxygen is generated or consumed in response to a reaction of theanalyte.

In certain embodiments, a catalyst may be attached to a polymer, crosslinking the catalyst with another electron transfer agent (which, asdescribed above, may be polymeric. A second catalyst may also be used incertain embodiments. This second catalyst may be used to catalyze areaction of a product compound resulting from the catalyzed reaction ofthe analyte. The second catalyst may operate with an electron transferagent to electrolyze the product compound to generate a signal at theworking electrode. Alternatively, a second catalyst may be provided inan interferent-eliminating layer to catalyze reactions that removeinterferents.

Certain embodiments include a Wired Enzyme™ sensing layer (AbbottDiabetes Care) that works at a gentle oxidizing potential, e.g., apotential of about +40 mV. This sensing layer uses an osmium (Os)-basedmediator designed for low potential operation and is stably anchored ina polymeric layer. Accordingly, in certain embodiments the sensingelement is redox active component that includes (1) Osmium-basedmediator molecules attached by stable (bidente) ligands anchored to apolymeric backbone, and (2) glucose oxidase enzyme molecules. These twoconstituents are crosslinked together.

A mass transport limiting layer (not shown), e.g., an analyte fluxmodulating layer, may be included with the sensor to act as adiffusion-limiting barrier to reduce the rate of mass transport of theanalyte, for example, glucose or lactate, into the region around theworking electrodes. The mass transport limiting layers are useful inlimiting the flux of an analyte to a working electrode in anelectrochemical sensor so that the sensor is linearly responsive over alarge range of analyte concentrations and is easily calibrated. Masstransport limiting layers may include polymers and may be biocompatible.A mass transport limiting layer may provide many functions, e.g.,biocompatibility and/or interferent-eliminating, etc.

In certain embodiments, a mass transport limiting layer is a membranecomposed of crosslinked polymers containing heterocyclic nitrogengroups, such as polymers of polyvinylpyridine and polyvinylimidazole.Embodiments also include membranes that are made of a polyurethane, orpolyether urethane, or chemically related material, or membranes thatare made of silicone, and the like.

A membrane may be formed by crosslinking in situ a polymer, modifiedwith a zwitterionic moiety, a non-pyridine copolymer component, andoptionally another moiety that is either hydrophilic or hydrophobic,and/or has other desirable properties, in an alcohol-buffer solution.The modified polymer may be made from a precursor polymer containingheterocyclic nitrogen groups. For example, a precursor polymer may bepolyvinylpyridine or polyvinylimidazole. Optionally, hydrophilic orhydrophobic modifiers may be used to “fine-tune” the permeability of theresulting membrane to an analyte of interest. Optional hydrophilicmodifiers, such as poly(ethylene glycol), hydroxyl or polyhydroxylmodifiers, may be used to enhance the biocompatibility of the polymer orthe resulting membrane.

A membrane may be formed in situ by applying an alcohol-buffer solutionof a crosslinker and a modified polymer over an enzyme-containingsensing layer and allowing the solution to cure for about one to twodays or other appropriate time period. The crosslinker-polymer solutionmay be applied to the sensing layer by placing a droplet or droplets ofthe solution on the sensor, by dipping the sensor into the solution, orthe like. Generally, the thickness of the membrane is controlled by theconcentration of the solution, by the number of droplets of the solutionapplied, by the number of times the sensor is dipped in the solution, orby any combination of these factors. A membrane applied in this mannermay have any combination of the following functions: (1) mass transportlimitation, i.e., reduction of the flux of analyte that can reach thesensing layer, (2) biocompatibility enhancement, or (3) interferentreduction.

The electrochemical sensors may employ any suitable measurementtechnique. For example, may detect current or may employ potentiometry.Technique may include, but are not limited to amperometry, coulometry,voltammetry. In some embodiments, sensing systems may be optical,colorimetric, and the like.

In certain embodiments, the sensing system detects hydrogen peroxide toinfer glucose levels. For example, a hydrogen peroxide-detecting sensormay be constructed in which a sensing layer includes enzyme such asglucose oxides, glucose dehydrogensae, or the like, and is positionedproximate to the working electrode. The sending layer may be covered bya membrane that is selectively permeable to glucose. Once the glucosepasses through the membrane, it is oxidized by the enzyme and reducedglucose oxidase can then be oxidized by reacting with molecular oxygento produce hydrogen peroxide.

Certain embodiments include a hydrogen peroxide-detecting sensorconstructed from a sensing layer prepared by crosslinking two componentstogether, for example: (1) a redox compound such as a redox polymercontaining pendent Os polypyridyl complexes with oxidation potentials ofabout +200 mV vs. SCE, and (2) periodate oxidized horseradish peroxidase(HRP). Such a sensor functions in a reductive mode; the workingelectrode is controlled at a potential negative to that of the Oscomplex, resulting in mediated reduction of hydrogen peroxide throughthe HRP catalyst.

In another example, a potentiometric sensor can be constructed asfollows. A glucose-sensing layer is constructed by crosslinking together(1) a redox polymer containing pendent Os polypyridyl complexes withoxidation potentials from about −200 mV to +200 mV vs. SCE, and (2)glucose oxidase. This sensor can then be used in a potentiometric mode,by exposing the sensor to a glucose containing solution, underconditions of zero current flow, and allowing the ratio ofreduced/oxidized Os to reach an equilibrium value. The reduced/oxidizedOs ratio varies in a reproducible way with the glucose concentration,and will cause the electrode's potential to vary in a similar way.

A sensor may also include an active agent such as an anticlotting and/orantiglycolytic agent(s) disposed on at least a portion a sensor that ispositioned in a user. An anticlotting agent may reduce or eliminate theclotting of blood or other body fluid around the sensor, particularlyafter insertion of the sensor. Examples of useful anticlotting agentsinclude heparin and tissue plasminogen activator (TPA), as well as otherknown anticlotting agents. Embodiments may include an antiglycolyticagent or precursor thereof. Examples of antiglycolytic agents areglyceraldehyde, fluoride ion, and mannose.

Sensors may be configured to require no system calibration or no usercalibration. For example, a sensor may be factory calibrated and neednot require further calibrating. In certain embodiments, calibration maybe required, but may be done without user intervention, i.e., may beautomatic. In those embodiments in which calibration by the user isrequired, the calibration may be according to a predetermined scheduleor may be dynamic, i.e., the time for which may be determined by thesystem on a real-time basis according to various factors, such as butnot limited to glucose concentration and/or temperature and/or rate ofchange of glucose, etc.

Calibration may be accomplished using an in vitro test strip (or otherreference), e.g., a small sample test strip such as a test strip thatrequires less than about 1 microliter of sample (for example FreeStyle®blood glucose monitoring test strips from Abbott Diabetes Care). Forexample, test strips that require less than about 1 nanoliter of samplemay be used. In certain embodiments, a sensor may be calibrated usingonly one sample of body fluid per calibration event. For example, a userneed only lance a body part one time to obtain sample for a calibrationevent (e.g., for a test strip), or may lance more than one time within ashort period of time if an insufficient volume of sample is firstlyobtained. Embodiments include obtaining and using multiple samples ofbody fluid for a given calibration event, where glucose values of eachsample are substantially similar. Data obtained from a given calibrationevent may be used independently to calibrate or combined with dataobtained from previous calibration events, e.g., averaged includingweighted averaged, etc., to calibrate. In certain embodiments, a systemneed only be calibrated once by a user, where recalibration of thesystem is not required.

Analyte systems may include an optional alarm system that, e.g., basedon information from a processor, warns the patient of a potentiallydetrimental condition of the analyte. For example, if glucose is theanalyte, an alarm system may warn a user of conditions such ashypoglycemia and/or hyperglycemia and/or impending hypoglycemia, and/orimpending hyperglycemia. An alarm system may be triggered when analytelevels approach, reach or exceed a threshold value. An alarm system mayalso, or alternatively, be activated when the rate of change, oracceleration of the rate of change, in analyte level increase ordecrease approaches, reaches or exceeds a threshold rate oracceleration. A system may also include system alarms that notify a userof system information such as battery condition, calibration, sensordislodgment, sensor malfunction, etc. Alarms may be, for example,auditory and/or visual. Other sensory-stimulating alarm systems may beused including alarm systems which heat, cool, vibrate, or produce amild electrical shock when activated.

The subject disclosure also includes sensors used in sensor-based drugdelivery systems. The system may provide a drug to counteract the highor low level of the analyte in response to the signals from one or moresensors. Alternatively, the system may monitor the drug concentration toensure that the drug remains within a desired therapeutic range. Thedrug delivery system may include one or more (e.g., two or more)sensors, a processing unit such as a transmitter, a receiver/displayunit, and a drug administration system. In some cases, some or allcomponents may be integrated in a single unit. A sensor-based drugdelivery system may use data from the one or more sensors to providenecessary input for a control algorithm/mechanism to adjust theadministration of drugs, e.g., automatically or semi-automatically. Asan example, a glucose sensor may be used to control and adjust theadministration of insulin from an external or implanted insulin pump.

In certain embodiments, an analyte signal processing method may includedetermining a measurement time period, receiving a plurality of signalsassociated with a monitored analyte level during the determinedmeasurement time period from an analyte sensor, modulating the receivedplurality of signals to generate a data stream over the measurement timeperiod, and accumulating the generated data stream to determine ananalyte signal corresponding to the monitored analyte level associatedwith the measurement time period.

Certain aspects may further include filtering the received plurality ofsignals associated with the monitored analyte level.

In certain embodiments, filtering may include bandpass filtering theplurality of signals.

In certain embodiments, modulating the received plurality of signals mayinclude synchronizing each of the received plurality of signals with acorresponding clock signal to generate a respective frequency pulse.

In certain embodiments, the accumulated data stream may includemaintaining a count of the number of generated frequency pulses duringthe measurement time period.

In certain embodiments, the determined analyte signal corresponding tothe monitored analyte level may include an average value of thegenerated frequency pulses.

In certain embodiments, the received plurality of signals may be voltagesignals, and further, modulating the generated data stream may includeconverting each of the voltage signals into a corresponding frequencypulse stream.

In certain aspects, the average of the frequency pulse stream for themeasurement time period may correspond to the determined analyte levelfor the measurement time period.

In certain embodiments, the measurement time period may be programmable.

In certain embodiments, the measurement time period may be modifiedbased at least in part on one or more characteristics of the analytesensor.

Certain aspects may further include removing one or more signalartifacts from the received plurality of signals.

In certain embodiments, removing the one or more signal artifacts mayinclude filtering the received plurality of signals prior to modulatingthe signals.

In certain embodiments, a signal processing device used for processinganalyte related signals may include an analyte sensor interfaceelectronics for receiving a plurality of analyte related signals from ananalyte sensor over a measurement time period, and a data processingcomponent operatively coupled to the analyte sensor interfaceelectronics for processing the received plurality of analyte relatedsignals, the data processing component including, a signal filteringcomponent to filter the received plurality of analyte related signals,and a signal conversion component operatively coupled to the signalfiltering component to convert the received filtered plurality ofanalyte related signals to determine an analyte level associated with amonitored analyte level during the measurement time period.

In certain embodiments, at least a portion of the one or more analytesensor interface electronics or the data processing components mayinclude an application specific integrated circuit.

In certain embodiments, the signal conversion component may include aclock to generate a plurality of clock signals.

In certain embodiments, the signal conversion component may synchronizeeach of the received filtered plurality of analyte related signals tothe corresponding one of the generated plurality of clock signals.

In certain embodiments, the signal conversion component may generate afrequency data stream based on the received filtered plurality ofanalyte related signals.

In certain embodiments, each pulse in the frequency data stream may beassociated with the respective one of the generated plurality of clocksignals.

In certain embodiments, the signal conversion component may include asigma delta modulation unit.

Certain aspects may include a communication component to transmit dataassociated with the determined analyte level over a communicationconnection.

In certain embodiments, the communication component may include an RFtransmitter.

In certain embodiments, the communication connection may include one ormore of a wired communication link or a wireless communication link.

In certain embodiments, the analyte sensor may include a glucose sensor.

In certain embodiments, the glucose sensor may include at least oneworking electrode in signal communication with the analyte sensorinterface electronics.

In certain embodiments, the working electrode of the sensor may includeone of carbon or gold.

In certain embodiments, an analyte monitoring system may include ananalyte sensor including a working electrode having a sensing layer atleast a portion of which is configured for fluid contact with an with aninterstitial fluid under a skin layer, and a data processing unitcomprising an application specific integrated circuit in signalcommunication with the analyte sensor for receiving a plurality ofsignals related to a monitored analyte level from the sensor over amonitoring time period, the data processing unit including a signalfiltering component to filter the received plurality of signals, and asignal conversion component to convert the received filtered pluralityof analyte related signals to determine a corresponding analyte levelassociated with a monitored analyte level during a measurement timeperiod, said monitoring time period including multiple measurement timeperiods.

In certain embodiments, the signal conversion component may include aclock to generate a plurality of clock signals.

In certain embodiments, the signal conversion component may synchronizeeach of the received filtered plurality of analyte related signals tothe corresponding one of the generated plurality of clock signals.

In certain embodiments, the signal conversion component may generate afrequency data stream based on the received filtered plurality ofanalyte related signals.

In certain embodiments, each pulse in the frequency data stream may beassociated with the respective one of the generated plurality of clocksignals.

In certain embodiments, the data processing unit may include a sigmadelta modulator.

In certain embodiments, the analyte sensor may include a glucose sensor.

In certain embodiments, the working electrode of the sensor may includeone of carbon or gold.

In certain embodiments, the sensing layer may include redox polymer.

In certain embodiments, the working electrode may be provided on theanalyte sensor using laser ablation or photolithography.

Certain aspects may further include a receiver unit in signalcommunication with the data processing unit to receive a plurality ofdata corresponding to the monitored analyte level from the sensor or thedata processing unit.

In certain embodiments, the receiver unit may include a strip port toreceive an in vitro glucose test strip.

In certain embodiments, the analyte sensor may be calibrated based onthe glucose measurement derived from the in vitro test strip.

In certain embodiments, the measurement time period may be approximately30 seconds.

In certain embodiments, the monitoring time period may be betweenapproximately five to seven days.

Various other modifications and alterations in the structure and methodof operation of the embodiments of the present disclosure will beapparent to those skilled in the art without departing from the scopeand spirit of the present disclosure. Although the present disclosurehas been described in connection with certain embodiments, it should beunderstood that the present disclosure as claimed should not be undulylimited to such embodiments. It is intended that the following claimsdefine the scope of the present disclosure and that structures andmethods within the scope of these claims and their equivalents becovered thereby.

1. An analyte signal processing method, comprising: determining ameasurement time period; receiving a plurality of signals associatedwith a monitored analyte level during the determined measurement timeperiod from an analyte sensor; modulating the received plurality ofsignals to generate a data stream over the measurement time period; andaccumulating the generated data stream to determine an analyte signalcorresponding to the monitored analyte level associated with themeasurement time period.
 2. The method of claim 1 including filteringthe received plurality of signals associated with the monitored analytelevel.
 3. The method of claim 2 wherein filtering including bandpassfiltering the plurality of signals.
 4. The method of claim 1 whereinmodulating the received plurality of signals includes synchronizing eachof the received plurality of signals with a corresponding clock signalto generate a respective frequency pulse.
 5. The method of claim 4wherein the accumulated data stream includes maintaining a count of thenumber of generated frequency pulses during the measurement time period.6. The method of claim 5 wherein the determined analyte signalcorresponding to the monitored analyte level includes an average valueof the generated frequency pulses.
 7. The method of claim 1 wherein thereceived plurality of signals are voltage signals, and further, whereinmodulating the generated data stream includes converting each of thevoltage signals into a corresponding frequency pulse stream.
 8. Themethod of claim 7 wherein the average of the frequency pulse stream forthe measurement time period corresponds to the determined analyte levelfor the measurement time period.
 9. The method of claim 1 wherein themeasurement time period is programmable.
 10. The method of claim 1wherein the measurement time period is modified based at least in parton one or more characteristics of the analyte sensor.
 11. The method ofclaim 1 including removing one or more signal artifacts from thereceived plurality of signals.
 12. The method of claim 11 whereinremoving the one or more signal artifacts includes filtering thereceived plurality of signals prior to modulating the signals.
 13. Asignal processing device used for processing analyte related signals,comprising: an analyte sensor interface electronics for receiving aplurality of analyte related signals from an analyte sensor over ameasurement time period; and a data processing component operativelycoupled to the analyte sensor interface electronics for processing thereceived plurality of analyte related signals, the data processingcomponent including: a signal filtering component to filter the receivedplurality of analyte related signals; and a signal conversion componentoperatively coupled to the signal filtering component to convert thereceived filtered plurality of analyte related signals to determine ananalyte level associated with a monitored analyte level during themeasurement time period.
 14. The device of claim 13 wherein at least aportion of the one or more analyte sensor interface electronics or thedata processing components includes an application specific integratedcircuit.
 15. The device of claim 13 wherein the signal conversioncomponent includes a clock to generate a plurality of clock signals. 16.The device of claim 15 wherein the signal conversion componentsynchronizes each of the received filtered plurality of analyte relatedsignals to the corresponding one of the generated plurality of clocksignals.
 17. The device of claim 16 wherein the signal conversioncomponent generates a frequency data stream based on the receivedfiltered plurality of analyte related signals.
 18. The device of claim17 wherein each pulse in the frequency data stream is associated withthe respective one of the generated plurality of clock signals.
 19. Thedevice of claim 13 wherein the signal conversion component includes asigma delta modulation unit.
 20. The device of claim 13 including acommunication component to transmit data associated with the determinedanalyte level over a communication connection.
 21. The device of claim20 wherein the communication component includes an RF transmitter. 22.The device of claim 20 wherein the communication connection includes oneor more of a wired communication link or a wireless communication link.23. The device of claim 13 wherein the analyte sensor includes a glucosesensor.
 24. The device of claim 23 wherein the glucose sensor includesat least one working electrode in signal communication with the analytesensor interface electronics.
 25. The device of claim 24 wherein theworking electrode of the sensor comprises one of carbon or gold.
 26. Ananalyte monitoring system, comprising: an analyte sensor including aworking electrode having a sensing layer at least a portion of which isconfigured for fluid contact with an with an interstitial fluid under askin layer; and a data processing unit comprising an applicationspecific integrated circuit in signal communication with the analytesensor for receiving a plurality of signals related to a monitoredanalyte level from the sensor over a monitoring time period, the dataprocessing unit including: a signal filtering component to filter thereceived plurality of signals; and a signal conversion component toconvert the received filtered plurality of analyte related signals todetermine a corresponding analyte level associated with a monitoredanalyte level during a measurement time period, said monitoring timeperiod including multiple measurement time periods.
 27. The system ofclaim 26 wherein the signal conversion component includes a clock togenerate a plurality of clock signals.
 28. The system of claim 27wherein the signal conversion component synchronizes each of thereceived filtered plurality of analyte related signals to thecorresponding one of the generated plurality of clock signals.
 29. Thesystem of claim 28 wherein the signal conversion component generates afrequency data stream based on the received filtered plurality ofanalyte related signals.
 30. The system of claim 29 wherein each pulsein the frequency data stream is associated with the respective one ofthe generated plurality of clock signals.
 31. The system of claim 26wherein the data processing unit includes a sigma delta modulator. 32.The system of claim 26 wherein the analyte sensor includes a glucosesensor.
 33. The system of claim 26 wherein the working electrode of thesensor comprises one of carbon or gold.
 34. The system of claim 26wherein the sensing layer includes redox polymer.
 35. The system ofclaim 26 wherein the working electrode is provided on the analyte sensorusing laser ablation or photolithography.
 36. The system of claim 26including a receiver unit in signal communication with the dataprocessing unit to receive a plurality of data corresponding to themonitored analyte level from the sensor or the data processing unit. 37.The system of claim 36 wherein the receiver unit includes a strip portto receive an in vitro glucose test strip.
 38. The system of claim 37wherein the analyte sensor is calibrated based on the glucosemeasurement derived from the in vitro test strip.
 39. The system ofclaim 26 wherein the measurement time period is approximately 30seconds.
 40. The system of claim 26 wherein the monitoring time periodis between approximately five to seven days.